Current medicinal chemistry最新文献

Mitochondria-associated membranes (MAMs) are pivotal in cellular homeostasis, mediating communication between the endoplasmic reticulum and mitochondria. They are increasingly recognized for their role in atherosclerosis and coronary artery disease (CAD). This review delves into the cellular perspective of MAMs' impact on atherosclerosis and CAD, highlighting their influence on disease progression and the potential for therapeutic intervention. MAMs are implicated in key pathophysiological processes such as the generation of reactive oxygen species, calcium homeostasis, myocardial ischemia-reperfusion injury, autophagy, lipid synthesis and transport, and energy metabolism-fundamental to the development and progression of atherosclerosis and CAD. The complex interplay of MAMs with these pathological processes underscores their potential as therapeutic targets. This review synthesizes current understanding and emphasizes the need for further research to elucidate the multifaceted roles of MAMs in atherosclerosis and CAD, offering avenues for developing novel strategies aimed at improving mitochondrial health and mitigating the impact of these conditions.

Aims: We aimed to develop a reliable prognostic tool related to glucagon-like peptide-1 (GLP-1) for guiding treatment of pancreatic cancer (PC).

Background: The treatment strategies for PC being greatly advanced the prognosis of cancer still remains unfavorable.

Objective: To develop a RiskScore model for evaluating PC prognosis.

Method: The bulk RNA-seq data of PC patients were obtained from the UCSCXena and GEO database, and the GSE156405 cohort was used for single-cell RNA-seq (scRNA- seq) analysis in the "Seurat" package. Firstly, the gene expression and mutation in the PC samples were analyzed to perform differentially expressed genes (DEGs) analysis using the "limma" package. The "survival" package was employed to conduct un/- multivariate Cox regression and Kaplan-Meier (KM) survival analysis. Secondly, a RiskScore model was developed and assessed using the "glmnet" and "timeROC" packages. Next, the CIBERSORT algorithm and the ssGSEA method were applied for immune infiltration analysis and calculation of the immune cell scores, respectively. Finally, pathway enrichment analysis was conducted using gene set enrichment analysis (GSEA).

Results: Most GLP-1 signaling genes were overexpressed in the PC samples with multiple mutation types. LASSO analysis selected 3 GLP-1 genes for the development of a RiskScore model with a high classification accuracy (AUC >0.6). Notably, high-risk patients showed a significantly shorter survival time in both training and validation sets. In addition, as an independent factor, the RiskScore was further used to establish a nomogram model for the survival prediction of PC in clinical practice. The tumor microenvironment (TME) analysis revealed that low-risk patients with more abundant immune and stroma components had higher levels of anti-tumor immune cell infiltration (such as activated B and T cells), while the proliferation pathways (E2F targets, G2M checkpoint) were significantly activated in the high-risk groups. The genes in the RiskScore model may affect the survival of PC patients through modulating the activities of NK cells and macrophages.

Conclusion: We demonstrated that the GLP-1 signaling affected PC development and developed a reliable RiskSocre model for the prognosis assessment in PC. Our findings are expected to improve PC diagnosis and treatment in clinical practice.

Recently, increasing attention has been directed toward nutraceuticals, natural substances extracted from plants, fruits, or cereals. These compounds are well-known for their antibacterial, anti-inflammatory, antioxidant, and antitumor properties, with the latter being the primary focus of this review. The use of nutraceuticals, both as standalone treatments and in combination with standard chemotherapy, has been extensively studied through in vitro, in vivo experiments, and clinical trials for the prevention and treatment of various types of cancer, including breast, colon, pancreatic, prostate cancers, and leukemia. Findings from these studies emphasize the benefits of nutraceuticals in improving patient compliance and mitigating the adverse effects of conventional drugs. Specifically, the combination of nutraceuticals with chemotherapy allows for reduced dosages of synthetic drugs, thereby lessening their often-severe side effects. In this review, we explore the diverse mechanisms of action underlying the antitumor activity of key nutraceuticals-including curcumin, resveratrol, tocotrienols, ursolic acid, fisetin, gambogic acid, catechins, silibinin, berberine, emodin, piperine, deguelin, garcinol, plumbagin, zerumbone, and ginger. Furthermore, we summarize the most significant outcomes from clinical trials investigating these compounds. The clinical studies addressed various aspects of treatment, such as efficacy, safety, maximum tolerated doses, potential adverse effects, and patient compliance. The majority of the findings highlight the positive impact of combining nutraceuticals with chemotherapy, demonstrating enhanced therapeutic outcomes in anticancer treatments.

Background: The high incidence of Non-Alcoholic Fatty Liver Disease (NAFLD) as a hepatic component of metabolic syndrome is attributed to the ongoing rise in obesity rates. Given the beneficial effects of hydroxychloroquine (HCQ) on metabolism, there is growing interest in combining it with fisetin (FSN), a natural product, to treat NAFLD more effectively.

Objective: The efficacy and safety of the combined therapy of FSN and HCQ in animal models of NAFLD were assessed, focusing on liver function, insulin sensitivity, oxidative stress, and inflammation.

Materials: and Methods: C57BL/6J mice were fed either a standard chow diet or a high- -fat diet to induce NAFLD. FSN and HCQ were administered to the mice, and biochemical parameters related to glucose and lipid metabolism, as well as oxidative stress markers, were measured in serum and liver tissue. Analyses included Oil Red O staining, mRNA levels of key lipid metabolism molecules, and immunohistochemical assessments of macrophage infiltration. Statistical analyses were performed using GraphPad Prism 9.

Results: While the HCQ group exhibited some improvements in certain markers, it also displayed adverse effects. The FSN group, particularly the FSN + HCQ group, effectively reversed insulin sensitivity, glucose homeostasis, and NAFLD markers by modulating lipid metabolism and inflammation pathways. HCQ exacerbated oxidative stress, which was mitigated by the effects of FSN.

Conclusion: Despite concerns regarding the long-term side effects of HCQ, its combination with FSN presents a promising approach for improving the management of NAFLD by reducing risks and enhancing outcomes.

The extracellular matrix (ECM) plays a pivotal role in maintaining tissue architecture and regulating cellular behavior. Recent insights have highlighted Discoidin Domain Receptors (DDRs) as critical mediators in cancer progression and therapeutic resistance. This editorial synthesizes the current understanding of DDR1 and DDR2, unique members of the receptor tyrosine kinase family activated by collagen, focusing on their distinct roles in cell-ECM interactions and cancer biology. We explore emerging therapeutic strategies targeting DDRs, with particular emphasis on differential approaches to DDR1 and DDR2 degradation. Additionally, we examine the complex relationship between DDR inhibition, degradation, and knockout phenotypes, presenting the novel DDR1 degrader LLC355 as a case study. By integrating findings from recent molecular investigations and clinical studies, we propose a comprehensive framework for DDRtargeted therapies in cancer treatment, highlighting their potential to overcome immune evasion mechanisms and enhance the efficacy of existing therapies.

Heart failure (HF), a widespread public health issue, affects about 26 million people all around the world, and its incidence and prevalence are still growing. Measuring serum biomarkers is beneficial in diagnosing HF and evaluating its prognosis. During the previous decade, various investigations have focused on identifying new HF biological markers that would have additional and/or superior prognostic, diagnostic, or classification value. While heart-specific biological markers, such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are commonly applied in clinical practice, there is still an unmet need for new markers in HF management. Insulin-like growth factor-binding protein-7 (IGFBP7), a cellular senescence marker, has been considered as a candidate biomarker in HF. This study aims to comprehensively reveal the underlying mechanism connecting IGFBP-7 to HF and review studies evaluating the prognostic or diagnostic performance of IGFBP-7 in combination with or in contrast with other potential HF biological markers. Increased IGFBP7 levels are associated with a set of functional and structural heart abnormalities such as diastolic dysfunction. Increased IGFBP7 concentrations seem to be an indicator of cardiac overload or injury and are related to HF major risk factors, including atherosclerosis, diabetes, and renal function. IGFBP7 is predictive of short and long-term outcomes in the HF population and can independently predict the rate of hospitalization and HF-related mortality.

Cyclin-dependent kinases that are responsible for the cell cycle control, have been studied for over 30 years as therapeutic targets for treatment cancer and inflammation. In past twenty years their activities in various viral infections have been investigated for search for novel therapeutic strategies in treatment of viral infections. The interest in evaluating the antiviral activity of cyclin-dependent kinase inhibitors is closely linked to their role as host factors in viral replication. Due to the development of viral resistance, the strategies directed onto the targeting host machinery are still under investigation. This review is dedicated to the analysis of the molecular mechanisms of viral infection control by cyclin-dependent kinases that may reveal the potential mechanisms of action for their inhibitors and regulators as antiviral agents. We also consider recent efforts and achievements in the development of potential antiviral agents based on the cyclin-dependent kinases inhibitors and regulators, including their effects on various viruses, side effects and toxicities.

Introductions: Sevoflurane, a commonly used anesthetic in surgery, can produce anesthetic effects such as sedation and muscle relaxation upon inhalation, which may lead to postoperative cognitive dysfunction. However, the molecular mechanism by which sevoflurane affects nervous system diseases like glioma remains unclear.

Method: In this study, we analyzed high-throughput single-cell transcriptome data of sevoflurane treatment and identified immune cells that play crucial roles in biological processes such as the immunoinflammatory response and the maintenance of the blood- -brain barrier. A total of 11,244 genes and their variations were obtained by analyzing the cell development trajectory. Additionally, 10 key genes affected by sevoflurane were manually retrieved, and their protein-protein interaction network was constructed. The Chinese Glioma Genome Atlas (CGGA) dataset was utilized for survival analysis.

Results: This article reveals that sevoflurane can generate anesthetic effects through signaling pathways such as the immunoinflammatory response, neuronal differentiation, and the maintenance of the blood-brain barrier, all of which have implications for organ injury and protection. Meanwhile, genes that play a key role in these immune pathways, such as the DAAM2 and EPHA3 genes, are significantly associated with the survival of glioma patients. This association implies that sevoflurane's influence on these genes might potentially affect postoperative cognitive dysfunction and the overall outcome of organ-organ interactions during and after surgery. Moreover, the experimental results demonstrated that sevoflurane inhibits the invasion and migration of glioma cells by suppressing the expression of EPHA3.

Conclusion: The discovery of this new target may pave the way for identifying causative gene regulation events and emphasize personalized treatments for nervous system diseases.

Background: Sepsis has a high mortality rate. While early diagnosis is crucial, there are no effective inflammatory or infectious markers for the diagnosis and prediction of sepsis.

Objective: The present study aimed to establish a correlation between inflammatory and infectious markers and the severity of sepsis at a genetic and cross-sectional level.

Methods: Using transcriptomic and clinical data from the GEO and Dryad databases, we analyzed the expression of eight indicators of inflammatory infection, as well as their diagnostic efficacy. Additionally, we investigated the correlation between eight plasma biomarkers and the Sequential Organ Failure Assessment (SOFA) score in sepsis.

Results: Angiotensin II (Ang-2), fractalkine, interleukin-1 receptor antagonist (IL-1ra), pentraxin 3 (PTX-3), and tumor necrosis factor (TNF)-α type 1 receptor (TNFR1) were up-regulated in sepsis and septic shock. Ang-2, IL-1ra, and PTX-3 had high diagnostic efficacy in both sepsis and septic shock. They also recruited chemokines to generate inflammatory storms, thereby exacerbating the progression of sepsis. Finally, we examined 153 adult non-trauma patients enrolled in the University of Pittsburgh Acute Lung Injury Registry (SOFA score > 2). Ang-2, suppressor of tumorigenicity 2 (ST-2), fractalkine, IL-1ra, TNFR1, procalcitonin (PCT), and PTX-3, but not C-peptide were significantly more expressed in the plasma of the severe sepsis group than in the mild sepsis group. Significant nonlinear correlations were detected between Ang-2, ST-2, IL-1ra, TNFR1, PCT, and PTX-3 levels and SOFA scores.

Conclusion: Our analysis revealed that Ang-2, IL-1ra, and PTX-3 correlated strongly with septic shock at the gene and protein levels, exhibiting nonlinear associations up to a certain point. These findings will facilitate the diagnosis and prognosis of septic shock.